Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase.
OBJECTIVE
Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model.


RESULTS
Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3-aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition, 3-aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrite-induced cytotoxicity in rat cardiac myocytes and human endothelial cells.


CONCLUSIONS
3-aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infarction.
Zingarelli
B
B
Children's Hospital Medical Center, Division of Critical Care, Cincinnati OH 45229, USA.
Cuzzocrea
S
S
Zsengellér
Z
Z
Salzman
A L
AL
Szabó
C
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C002744:3-nitrotyrosine; D014443:Tyrosine; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D009195:Peroxidase; D003402:Creatine Kinase